Cancer is a general term used when referring to any disease state that results from an abnormal uncontrolled and progressive cellular growth. There are presently three principal methods available for the treatment of cancer. These methods are surgery, radiotherapy and chemotherapy. Typically, though surgery and radiotherapy may be effective by themselves, chemotherapy is usually administered in combination therewith to assure favorable results. A common example of such a combination would be the utilization of surgery to remove a tumor followed by treatment with certain chemicals capable of controlling or eliminating remaining cells which may move through the body to seed the growth of additional tumor sites (metastasis). Thus, typically a heavy reliance is placed on chemotherapy regardless of the treatment selected.
Unfortunately, such treatment with chemicals (chemotherapy) continues to have very serious disadvantages. In particular, none of the approximately 30 drugs commonly used in cancer chemotherapy have proven to be capable of eliminating the cancer disease except in a relatively small number of isolated cases. Furthermore, most of the commonly used chemicals have very high toxicity or serious side effects relative to the dosage required to be effective against the abnormal tumor or growth (neoplasm). The use of prior art chemicals in chemotherapy, therefore, very often results in serious complications which endanger the human being or other host organism being treated. These disadvantages of cancer treating chemicals (antineoplastic drugs) continue despite the fact that many thousands of potential antineoplastic agents have been screened and tested.
Many of the effective antineoplastic agents are classified as alkylating agents, i.e. a substance which introduces an alkyl, or substituted alkyl radical into a compound in place of a hydrogen atom. In chemicals utilized for treating cancer such alkylation frequently occurs within a nucleic acid structure such as DNA or RNA of the cancer cell thus effectively preventing the cell from functioning or reproducing.
A number of such alkylating agents contain one or more aziridine rings or contain intermediate structures which can yield aziridine rings. An aziridine ring is a three-membered heterocyclic ring containing one nitrogen atom and two carbon atoms. Examples of alkylating chemicals which contain aziridine rings or contain structures which can yield aziridine rings are as follows: ##STR2## These compounds are believed to open at the aziridine ring site, if they are not already open, and then combine with a biological target molecules usually a nucleic acid, or, to be susceptible to nucleophilic displacement of the nitrogen from an aziridine ring carbon by a biological taret nucleophile, such as a nucleoside base, to interrupt the replication of the nucleic acid or to interfere with messages which would be transmitted by the nucleic acid.
In addition to the Thio-TEPA and TEPA compounds, numerous other phosphoaziridines are known. Phosphoaziridines are described in numerous publications, for example, in U.S. Pat. No. 2,606,900 to Parker et al; U.S. Pat. No. 3,201,313; to Bardos et al; in the Journal of Surgical Oncology 3(4) at pp 431-441 (1971) by Bardos et al; by Kimler et al in Radiology, 133 at pp 515-517 (1979); by Bardos et al in the International Journal of Radiation Oncology Biological Physics, Volume 5 at pp 1653-1656 (1979); by Wampler et al in International Journal of Radiation Oncology Biological Physics, Volume 5 at pp 1681-1683 (1979); and by Chmielewicz et al in the Journal of Pharmaceutical Sciences, Volume 56, No. 9 at pp 1179-1181 (1967).
Initially, phosphoaziridines were considered and classified as alkylating agents. In some cases, the diaziridinyl phosphinoyl group was chemically combined through an amide linkage to ethyl carbamate in an attempt to obtain a synergistic effect between the phosphoaziridine and urethane group. Such compounds derived from unsubstituted aziridines demonstrate potent anti-tumor activity but showed no significant clinical advantage over other alkylating agents.
Bis(2,2-dimethyl-1-aziridinyl) phosphinates were subsequently developed which showed the interesting characteristic of not only being chemicals suitable for chemotherapy but demonstrated the ability to potentiate the therapeutic effects of radiation upon transplated tumors. The Bis(2,2-dimethyl-1-aziridinyl)phosphinates which are connected with urethane groups nevertheless show highly effective antitumor activity with remarkably low toxicity for inhibiting the production and development of blood cells (hematopoietic toxicity) when compared with conventional alkylating agents.